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Science 308 (5728): 1626-1629

Copyright © 2005 by the American Association for the Advancement of Science

TLR11 Activation of Dendritic Cells by a Protozoan Profilin-Like Protein

Felix Yarovinsky,1* Dekai Zhang,3 John F. Andersen,2 Gerard L. Bannenberg,4{dagger} Charles N. Serhan,4 Matthew S. Hayden,3 Sara Hieny,1 Fayyaz S. Sutterwala,3 Richard A. Flavell,3 Sankar Ghosh,3 Alan Sher1*

Abstract: Mammalian Toll-like receptors (TLRs) play an important role in the innate recognition of pathogens by dendritic cells (DCs). Although TLRs are clearly involved in the detection of bacteria and viruses, relatively little is known about their function in the innate response to eukaryotic microorganisms. Here we identify a profilin-like molecule from the protozoan parasite Toxoplasma gondii that generates a potent interleukin-12 (IL-12) response in murine DCs that is dependent on myeloid differentiation factor 88. T. gondii profilin activates DCs through TLR11 and is the first chemically defined ligand for this TLR. Moreover, TLR11 is required in vivo for parasite-induced IL-12 production and optimal resistance to infection, thereby establishing a role for the receptor in host recognition of protozoan pathogens.

1 Immunobiology Section, Laboratory of Parasitic Diseases; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
2 Medical Entomology Section, Laboratory of Malaria and Vector Research; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
3 Section of Immunobiology and Department of Molecular Biophysics and Biochemistry, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA.
4 Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

{dagger} Present address: Departamento Genética Molecular de Plantas, Centro Nacional de Biotecnología, 28049 Madrid, Spain.

* To whom correspondence should be addressed. E-mail: asher{at} (A.S.); fyarovinsky{at} (F.Y.)

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J. Virol. 80, 9943-9950
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Toxoplasma gondii Genotype Determines MyD88-Dependent Signaling in Infected Macrophages.
L. Kim, B. A. Butcher, C. W. Lee, S. Uematsu, S. Akira, and E. Y. Denkers (2006)
J. Immunol. 177, 2584-2591
   Abstract »    Full Text »    PDF »
Invited review: Roles for accessory molecules in microbial recognition by Toll-like receptors.
K. Miyake (2006)
Innate Immunity 12, 195-204
   Abstract »    PDF »
New insights into the regulation of TLR signaling.
S. M. Miggin and L. A. J. O'Neill (2006)
J. Leukoc. Biol. 80, 220-226
   Abstract »    Full Text »    PDF »
Toxoplasma gondii Inhibits Toll-Like Receptor 4 Ligand-Induced Mobilization of Intracellular Tumor Necrosis Factor Alpha to the Surface of Mouse Peritoneal Neutrophils.
S. Bennouna, W. Sukhumavasi, and E. Y. Denkers (2006)
Infect. Immun. 74, 4274-4281
   Abstract »    Full Text »    PDF »
Cutting Edge: Dendritic Cells Are Essential for In Vivo IL-12 Production and Development of Resistance against Toxoplasma gondii Infection in Mice.
C.-H. Liu, Y.-t. Fan, A. Dias, L. Esper, R. A. Corn, A. Bafica, F. S. Machado, and J. Aliberti (2006)
J. Immunol. 177, 31-35
   Abstract »    Full Text »    PDF »
Distinct indirect pathways govern human NK-cell activation by TLR-7 and TLR-8 agonists.
K. S. Gorski, E. L. Waller, J. Bjornton-Severson, J. A. Hanten, C. L. Riter, W. C. Kieper, K. B. Gorden, J. S. Miller, J. P. Vasilakos, M. A. Tomai, et al. (2006)
Int. Immunol. 18, 1115-1126
   Abstract »    Full Text »    PDF »
Expression of Toll-Like Receptors (TLR) and Responsiveness to TLR Agonists by Polarized Mouse Uterine Epithelial Cells in Culture.
G. Soboll, L. Shen, and C. R. Wira (2006)
Biol Reprod 75, 131-139
   Abstract »    Full Text »    PDF »
TLR9 Is Required for the Gut-Associated Lymphoid Tissue Response following Oral Infection of Toxoplasma gondii..
L. A. Minns, L. C. Menard, D. M. Foureau, S. Darche, C. Ronet, D. W. Mielcarz, D. Buzoni-Gatel, and L. H. Kasper (2006)
J. Immunol. 176, 7589-7597
   Abstract »    Full Text »    PDF »
Recombinant Eimeria Protozoan Protein Elicits Resistance to Acute Phlebovirus Infection in Mice but Not Hamsters.
B. B. Gowen, D. F. Smee, M.-H. Wong, J. W. Judge, K.-H. Jung, K. W. Bailey, A. M. Pace, B. Rosenberg, and R. W. Sidwell (2006)
Antimicrob. Agents Chemother. 50, 2023-2029
   Abstract »    Full Text »    PDF »
Invited review: Tolerance to microbial TLR ligands: molecular mechanisms and relevance to disease.
A. E. Medvedev, I. Sabroe, J. D. Hasday, and S. N. Vogel (2006)
Innate Immunity 12, 133-150
   Abstract »    PDF »
Toxoplasma gondii triggers Gi-dependent PI 3-kinase signaling required for inhibition of host cell apoptosis.
L. Kim and E. Y. Denkers (2006)
J. Cell Sci. 119, 2119-2126
   Abstract »    Full Text »    PDF »
Invited review: MDP and other muropeptides direct and synergistic effects on the immune system.
S. Traub, S. von Aulock, T. Hartung, and C. Hermann (2006)
Innate Immunity 12, 69-85
   Abstract »    PDF »

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